Abstract

OBJECTIVE Kidney disease manifests clinically as elevated albumin excretion rate (AER), impaired glomerular filtration rate (GFR),
or both, and is a cause of substantial morbidity and mortality in type 1 diabetes (T1D). The Diabetes Control and Complications
Trial/Epidemiology of Diabetes Interventions and Complications (DCCT/EDIC) study tested whether intensive diabetes therapy
(INT) aimed at lowering glucose concentrations as close as safely possible to the normal range reduces the risks of kidney
disease and other diabetes complications.

RESEARCH DESIGN AND METHODS In the DCCT, 1,441 participants with T1D were randomly assigned to INT or conventional diabetes therapy (CON) for a mean
duration of 6.5 years. Subsequently, participants have been followed for 18 years in the ongoing observational EDIC. Standardized
longitudinal measurements of AER, estimated GFR, and blood pressure were made throughout the DCCT/EDIC.

Introduction

Kidney disease manifests clinically as elevated albumin excretion rate (AER), impaired glomerular filtration rate (GFR), or
both, and is a cause of substantial morbidity and mortality in type 1 diabetes (T1D). In early cohort studies, up to 40% of
patients with T1D developed macroalbuminuria (AER ≥300 mg/24 h), and up to 75% of these patients progressed to end-stage renal
disease (ESRD) within 10 years (1,2). Moreover, the presence and severity of kidney disease have been consistently and strongly associated with increased risks
of cardiovascular disease (CVD) and death (3,4).

A large body of evidence demonstrates that hyperglycemia contributes to the damage of target organs, including the kidney
(5). Moreover, poor glycemic control has been consistently associated with increased risk of developing kidney disease in T1D
(2,6). The Diabetes Control and Complications Trial (DCCT) tested the hypothesis that intensive diabetes therapy (INT) aimed at
lowering glucose concentrations as close as safely possible to the normal range would reduce the risk of developing microalbuminuria
(AER ≥40 mg/24 h), macroalbuminuria, and other complications of T1D, compared with conventional therapy (CON) (7). The Epidemiology of Diabetes Interventions and Complications (EDIC) study—the observational study following the DCCT—has
examined and continues to examine the extent to which the effects of INT observed during the DCCT are durable (8). In addition, the EDIC has examined the long-term effects of INT on related outcomes, such as impaired GFR and hypertension,
as well as the evolving clinical course of kidney disease in T1D. This article summarizes the most important published DCCT/EDIC
findings related to kidney disease.

Research Design and Methods

The DCCT enrolled 1,441 people with T1D from 1983–1989 to determine the effects of INT on the long-term complications of diabetes
(7,9). The trial included two cohorts. The primary prevention cohort was characterized by diabetes duration 1–5 years, AER <40
mg/24 h, and no retinopathy by fundus photography. The secondary intervention cohort was characterized by diabetes duration
1–15 years, AER ≤200 mg/24 h, and at least one microaneurysm in either eye (but no more than moderate nonproliferative retinopathy).
For both cohorts, serum creatinine <1.2 mg/dL or creatinine clearance >100 mL/min/1.73 m2 was required for eligibility. Hypertension, defined as systolic blood pressure ≥140 mmHg, diastolic blood pressure ≥90 mmHg,
or treatment with antihypertensive medications, was an exclusion criterion.

Participants were randomly assigned to receive INT or CON, as described in detail elsewhere (7,9). The DCCT ended in 1993 after a mean duration of 6.5 years. Subsequently, all surviving participants were invited to join
the observational EDIC, which continues today. During EDIC, mean HbA1c levels, which were separated by ∼2% during DCCT, became similar for the two original DCCT treatment groups (8).

AER was measured yearly during DCCT and every other year during EDIC using supervised 4-h urine collections (10,11). Water intake was encouraged to maintain urine output throughout the collection period. Urine albumin was measured at the
DCCT/EDIC Central Biochemistry Laboratory (CBL) at the University of Minnesota using a fluoroimmunoassay (interassay coefficient
of variation 8.4%).

Serum creatinine was measured annually throughout DCCT/EDIC at the CBL (interassay coefficient of variation <3%). All results
were calibrated to National Institute of Standards and Technology isotope dilution mass spectrometry assigned values (12). The Chronic Kidney Disease Epidemiology Collaboration equation was used to estimate GFR from calibrated serum creatinine,
age, sex, and race (13).

Blood pressure was measured every 3 months during DCCT and yearly during EDIC. Hypertension was defined as two consecutive
study visits with systolic blood pressure ≥140 mmHg, diastolic blood pressure ≥90 mmHg, or the use of antihypertensive medications
(14).

The effects of DCCT INT on AER, estimated GFR, and hypertension were tested according to intention to treat. Hazard ratios
(HRs) were estimated using Cox proportional hazards models, which incorporated death as a competing risk when evaluating impaired
GFR as the outcome (12). Risk reduction associated with INT was calculated as (1 − HR of INT vs. CON) × 100%. Proportion of effect explained by
DCCT HbA1c was the proportion of INT effect explained by statistical adjustment for the treatment group difference in DCCT mean HbA1c. Cumulative incidence of microalbuminuria or macroalbuminuria by diabetes duration was quantified using a nonparametric estimator
that allows for interval-censored observations (15,16).

Effects of INT on the development of microalbuminuria and macroalbuminuria during the DCCT and during EDIC years 1–8

During EDIC years 1–8, among participants who did not develop microalbuminuria during the DCCT, participants previously assigned
to DCCT INT continued to experience a lower risk of incident microalbuminuria (risk reduction 59% [95% CI 39–73%]) (8). The effects of INT on micro‐albuminuria during the DCCT and EDIC were largely explained by group differences in mean DCCT
HbA1c (Table 1).

During EDIC years 1–8, among participants who did not develop macroalbuminuria during the DCCT, participants previously assigned
to DCCT INT had an 84% lower risk of developing incident macroalbuminuria (95% CI 67–92%) (8). As with microalbuminuria, the effects of INT on macroalbuminuria were largely explained by group differences in mean DCCT
HbA1c (Table 1).

Adjustment for DCCT mean HbA1c fully explained the effect of INT on impaired GFR. In parallel, adjustment for updated mean AER explained 90% of the effect
of INT on impaired GFR (12). Relative risk reductions for more advanced stages of GFR loss were similar in magnitude to those for estimated GFR <60
mL/min/1.73 m2 (Table 2). However, these risk reductions were not all statistically significant, likely due to small numbers of events. INT reduced
the risk of a composite outcome of impaired GFR or death, demonstrating that beneficial effects on impaired GFR were not attributable
to a possible competing risk of death.

Effects of INT on the development of impaired GFR during the DCCT/EDIC

Hypertension

From DCCT baseline through EDIC year 12, 630 participants developed incident hypertension (Fig. 2) (14). During DCCT, the incidence of hypertension was similar in INT and CON treatment groups. However, INT during the DCCT reduced
the risk of incident hypertension during EDIC follow-up. Over combined DCCT/EDIC follow-up, INT reduced the risk of hypertension
by 20% (95% CI 6–21%). Adjustment for treatment group differences in DCCT mean HbA1c fully explained the effect of INT on incident hypertension. Parallel analyses suggested that AER explained a smaller portion
of the effect of INT on hypertension and that weight gain with INT slightly blunted the effect on hypertension that would
have otherwise been seen (14).

Clinical Course

The detailed long-term data collected during DCCT/EDIC have enabled assessment of the clinical course of kidney disease in
T1D. These analyses suggest that INT has modified the clinical course of kidney disease and have allowed further characterization
of disease progression in this population.

Thirty years after diabetes diagnosis, the cumulative incidences of microalbuminuriaand macroalbuminuria were lower among
participants assigned to INT versus CON. The 30-year cumulative incidence of microalbuminuria, defined for the observational
analyses as sustained AER ≥30 mg/24 h to be consistent with recent guidelines (18,19), was 25 or 38% among participants assigned to INT or CON, respectively (Fig. 3) (15). Similarly, the 30-year cumulative incidence of macroalbuminuria or worse, defined for this analysis as AER ≥300 mg/24 h
or serum creatinine ≥2 mg/dL, was 9 or 25%, respectively (16).

Cumulative incidence of persistent microalbuminuria (AER ≥30 mg/24 h on two consecutive study visits) in the DCCT/EDIC, by
duration of T1D and DCCT treatment assignment. Reproduced with permission from de Boer et al. (15).

Renal outcomes after developing microalbuminuria were variable in the DCCT/EDIC. Ten years after developing persistent microalbuminuria,
28, 15, and 4% of participants went on to develop macroalbuminuria, impaired GFR, and ESRD, respectively (Fig. 4) (15). However, 40% of participants with incident microalbuminuria regressed to persistent AER <30 mg/24 h. Lower HbA1c was associated with more favorable renal outcomes after microalbuminuria diagnosis.

Cumulative incidence of long-term renal outcomes after the development of persistent microalbuminuria (AER ≥30 mg/24 h on
two consecutive study visits, defining time 0) among 325 participants in the DCCT/EDIC. Normoalbuminuria (AER <30 mg/24 h
on two consecutive study visits), macroalbuminuria (AER ≥300 mg/24 h), impaired GFR (estimated GFR <60 mL/min/1.73 m2 on two consecutive study visits), and ESRD are evaluated as parallel outcomes and are not mutually exclusive. Reproduced
with permission from de Boer et al. (15).

Macroalbuminuria was more strongly associated than microalbuminuria with GFR loss in the DCCT/EDIC. Mean rate of change in
estimated GFR was 5.7% per year (95% CI 4.5–6.8%) in subjects who developed macroalbuminuria, compared with 1.2% per year
(1.2–1.3%) with AER <30 mg/24 h and 1.8% per year (1.6–1.9%) in subjects with microalbuminuria (20). Moreover, macroalbuminuria was associated with a more than a 15-fold increase in risk of developing impaired GFR (HR 15.3
[95% CI 8.9–26.3]). Sixty-one percent of participants who developed impaired GFR first developed macroalbuminuria.

Additional work has identified genetic predisposition, male sex, obesity, blood pressure, inflammation, vitamin D deficiency,
and dyslipidemia as risk factors for the development and progression of kidney disease in DCCT/EDIC (15,21–28).

Kidney and CVD

In EDIC, higher AER and higher blood pressure were associated with greater common and internal carotid intima-media thickness,
a greater prevalence and severity of coronary artery calcium, reduced compliance of the aorta, and greater left ventricular
mass (29–32). Moreover, during the combined DCCT/EDIC, microalbuminuria and macroalbuminuria were associated with nearly threefold increased
risks of clinical CVD events (HR 2.93 [95% CI 1.85–4.65] and 2.57 [1.36–4.88], respectively) (33). Adjustment for treatment group differences in microalbuminuria and macroalbuminuria explained a minority of the beneficial
effect of INT on risk of clinical CVD events.

Conclusions

In the DCCT/EDIC, INT resulted in substantial, durable reductions in the risks of microalbuminuria, macroalbuminuria, impaired
GFR, and hypertension. For microalbuminuria and macroalbuminuria, beneficial effects were observed during the DCCT. Moreover,
during EDIC follow-up, the incidences of microalbuminuria and macroalbuminuria continued to be lower among participants previously
assigned to DCCT INT, with risk reductions during EDIC years 1–8 that were even greater than those observed during the DCCT
itself. For impaired GFR and hypertension, beneficial effects of INT were not observed during the DCCT, but significant effects
became apparent during long-term EDIC follow-up. The cumulative incidences of microalbuminuria and macroalbuminuria 30 years
after diagnosis of diabetes were substantially lower among participants assigned to INT versus CON, providing further evidence
that early INT alters the clinical course of kidney disease in T1D.

The term “metabolic memory” has been used to describe the differences in outcomes that persist or even expand after the original
separation in chronic glycemia, based on treatment assignment, has disappeared. The persistent effects of INT on microalbuminuria
and macroalbuminuria during EDIC years 1–8 are striking examples of this phenomenon. The subsequent beneficial effects of
INT on impaired GFR and hypertension represent the long-term consequences of INT. The biological basis of metabolic memory
remains a matter of speculation. Clinically, the important implication is that INT applied early in the course of T1D has
strong and long-lasting effects to reduce the long-term risks of kidney disease.

Importantly, the DCCT/EDIC evaluated the effects of INT on each of the two most important clinical features of diabetic kidney
disease—albuminuria and impaired GFR. To our knowledge, INT is the only intervention that has been demonstrated to reduce
the risks of developing both albuminuria (microalbuminuria or macroalbuminuria) and impaired GFR in T1D. This emphasizes the
importance of hyperglycemia in the pathophysiology of kidney disease in T1D and the primary role for glucose control in preventing
both major manifestations of diabetic kidney disease in this population.

The beneficial effects of INT on the risks of microalbuminuria, macroalbuminuria, and impaired GFR were fully attenuated by
statistical adjustment for HbA1c. Interestingly, in parallel, the beneficial effects of INT on the risk of impaired GFR were also fully attenuated by statistical
adjustment for AER. This suggests that a common set of disease mechanisms leading from hyperglycemia to both albuminuria and
impaired GFR is interrupted by INT. Additional observations from the DCCT/EDIC suggest that other mechanisms also contribute
to the development of microalbuminuria, macroalbuminuria, and impaired GFR, and that these mechanisms may vary by disease
manifestation. Most participants who developed microalbuminuria did not go on to develop impaired GFR, and most but not all
participants who developed impaired GFR first developed macroalbuminuria. Blood pressure, obesity, and other metabolic factors
appear to influence the development of kidney disease in T1D, in addition to hyperglycemia. These risk factors may offer additional
treatment options to prevent and treat kidney disease in T1D, in addition to intensive glucose control.

Higher AER and blood pressure were associated with increased risks of CVDs, including carotid atherosclerosis, coronary atherosclerosis,
stiffening of the aorta, and left ventricular hypertrophy. Taken together with similar observations in other cohorts (34,35), these results suggest a central role for kidney disease in the macrovascular complications of T1D. The beneficial effects
of INT on kidney disease and blood pressure would therefore be expected to yield subsequent reductions in the risks of CVD.
Statistical modeling suggested that reductions in AER explained a minority of the beneficial effects of INT on clinical CVD
events, but such mediation analyses can underestimate the impact of covariates. Future studies will further evaluate the impact
of kidney disease on CVD in the DCCT/EDIC, including the extent to which reductions in kidney disease with INT affect risk
of CVD over long-term follow-up.

Strengths of the DCCT/EDIC include its randomized, controlled design with substantial separation in HbA1c achieved by treatment assignment; the detailed longitudinal characterization of diabetes complications; and the unusually
long duration of follow-up, particularly for a clinical trial. These strengths were made possible by dedicated research staff,
consistent sponsor support, and, most important, the invaluable contributions of the DCCT/EDIC participants. Low numbers of
ESRD and CVD events have limited analyses of these outcomes to date. Continued follow-up of the DCCT/EDIC cohort will facilitate
further examination of these events in the future.

In conclusion, INT applied early in the course of T1D resulted in clinically important, long-lasting reductions in the incidence
of kidney disease. These benefits, combined with congruent reductions in the risks of retinopathy, neuropathy, CVD, and other
diabetes complications, serve as a cornerstone of recommendations to control glycemia in T1D.

Article Information

Funding. The DCCT/EDIC has been supported by U01 Cooperative Agreement grants (1982–1993, 2011–2016) and contracts (1982–2011) with
the Division of Diabetes Endocrinology and Metabolic Diseases of the National Institute of Diabetes and Digestive and Kidney
Diseases (current grant numbers U01-DK-094176 and U01-DK-094157) and through support of the National Eye Institute, the National
Institute of Neurological Disorders and Stroke, the Genetic Clinical Research Centers Program (1993–2007), and Clinical and
Translational Science Center Program (2006–present), Bethesda, MD. I.H.d.B. was supported by grants R01-DK-087726, R01-DK-088762,
and RC4-DK-090766 from the National Insititute of Diabetes and Digestive and Kidney Diseases.

Duality of Interest. No potential conflicts of interest relevant to this article were reported.

Author Contributions. The DCCT/EDIC Research Group collected and analyzed the data. I.H.d.B. participated in data collection and analysis, and
wrote the manuscript. I.H.d.B. is the guarantor of this work and, as such, had full access to all the data in the study and
takes responsibility for the integrity of the data and the accuracy of the data analysis.

. In the absence of renal disease, 20 year mortality risk in type 1 diabetes is comparable to that of the general population:
a report from the Pittsburgh Epidemiology of Diabetes Complications Study. Diabetologia2010;53:2312–2319pmid:20665208

Writing Team for the Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications Research
Group

. Sustained effect of intensive treatment of type 1 diabetes mellitus on development and progression of diabetic nephropathy:
the Epidemiology of Diabetes Interventions and Complications (EDIC) study. JAMA2003;290:2159–2167pmid:14570951

. Baseline analysis of renal function in the Diabetes Control and Complications Trial. The Diabetes Control and Complications Trial Research Group. [published correction appears in Kidney Int 1993;43:1196]. Kidney Int1993;43:668–674pmid:8455366

Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications Study Research Group

. Long-term renal outcomes of patients with type 1 diabetes mellitus and microalbuminuria: an analysis of the Diabetes Control
and Complications Trial/Epidemiology of Diabetes Interventions and Complications cohort. Arch Intern Med2011;171:412–420pmid:21403038

. Development and progression of renal insufficiency with and without albuminuria in adults with type 1 diabetes in the Diabetes
Control and Complications Trial and the Epidemiology of Diabetes Interventions and Complications Study. Diabetes Care2010;33:1536–1543pmid:20413518

Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications Research Group

. Multiple superoxide dismutase 1/splicing factor serine alanine 15 variants are associated with the development and progression
of diabetic nephropathy: the Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications
Genetics study. Diabetes2008;57:218–228pmid:17914031

. The effect of intensive glycemic treatment on coronary artery calcification in type 1 diabetic participants of the Diabetes
Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications (DCCT/EDIC) Study. Diabetes2006;55:3556–3565pmid:17130504

Related articles

DCCT/EDIC 30th Anniversary Summary Findings:

William T. Cefalu and

Robert E. Ratner

The Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications Study at 30 Years: The
“Gift” That Keeps on Giving! Diabetes Care January 2014 37:1 5-7; doi:10.2337/dc13-2369

Diabetic Retinopathy and Other Ocular Findings in the Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions
and Complications Study Diabetes Care January 2014 37:1 17-23; doi:10.2337/dc13-2251

Neuropathy and Related Findings in the Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and
Complications Study Diabetes Care January 2014 37:1 31-38; doi:10.2337/dc13-2114

Update on Cardiovascular Outcomes at 30 Years of the Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions
and Complications Study Diabetes Care January 2014 37:1 39-43; doi:10.2337/dc13-2116